Fluoroalkyl Amino Acids

Due to the absence of a hydrogen atom on the a-carbon, the a-fluoroalkyl amino acids (except, of course, the fluoroalanines, vide supra) cannot undergo an elimination of HR Consequently, they are more stable than fluoroalanines and other jS-fluoro amino acids previously described. On the other hand, similar to proteogenic amino acids, jS-fluoro amino acids and a-fluoroalkyl amino acids are generally substrates of pyridoxal phosphate depending on enzymes such as racemases and decarboxylases. When an amino acid is a substrate of such enzymes, the enzyme induces the development of a negative charge on the a-carbon, which can initiate a /(-elimination process. This reaction affords an electrophilic species (Michael acceptor type), which is able to add a nucleophilic residue of the enzyme. This notion of mechanism-based inhibitor is detailed in Chapter 7. 

Generally, the a-fluoroalkyl amino acids cannot be prepared by means of classical methods. Thus, original methods for their synthesis have been required and set up.  

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The orthogonal properties of fluoroalkyl amino acid side chains 747... 

In the previous chapter we described a systematic study of the interactions of small model peptides with a rather specific enzyme. In our attempt to systematize the effects of fluorinated amino acids on peptide and protein interactions we have established a model system that lays the foundation for a more general approach. How do the steric effects and the degree of fluorination as well as the polarity of fluoroalkyl amino acid side chains affect the folding of proteins and the strength of peptide-protein interactions In order to answer this central question we choose a very common folding motive, the a-helical coiled coil. 

Being highly hydrophobic but less lipophilic than their hydrocarbon analogs, fluoroalkyl amino acid side chains tend to interact with one another by fluorine-fluorine contacts. Therefore, even one single fluorinated amino acid can direct polypeptide folding due to strong character of fluorine-fluorine interactions (Section 3.3 and 3.4). 

R. Smits, B. Koksch, How C -fluoroalkyl amino acids and peptides interact with enzymes Studies concerning the influence on proteolytic stability, enzymatic resolution and peptide coupling, Curr. Top. Med. Chem. 6(14) (2006) 1483-1498. 

Soloshonok and co-workers have demonstrated that the racemic /(-(perfluoroalkyl)-/ -amino acids obtained from the 1,3-proton shift reaction can be resolved biocatalytically as the 7V-(phenylacetyl)-substituted derivatives using penicillin acylase.20 -22 An attempt has also been made to carry out an asymmetric 1,3-proton shift reaction to synthesize chiral / -(per-fluoroalkyl)-/ -amino acids directly.23 24 The isomerization has been carried out on enamines 29a-c, e, and f using ( —)-cinchonidinc as chiral base, giving the corresponding ben-zylideneamines 31 a-c, e, and f in 67-89 % yield. The /5-(perfluoroalkyl)-/,y-aniino acids 32a-c, e, and f are obtained in 88 — 93 % yield, but in only 16-36%ee of the /Cisomer.23 24... 

Konno, T., Daitoh, T., Ishihara, T. and Yamanaka, H. (2001) A novel and expedient synthesis of optically active fluoroalkylated amino acids via palladium-catalyzed allylic rearrangement and Ireland-Claisen rearrangement. Tetrahedron Asymmetry, 12, 2743-2748. 

Thurst S, Koksche B (2003) Protease-catalysed peptide synthesis for the site specific incorporation of alpha-fluoroalkyl amino acids into peptides. J Org Chem 68 2290-2296 Trusek-Holownia A (2003) Synthesis of Z-Ala-Phe.OMe, the precursor of bitter dipeptide in the two-phase ethyl acetate-water system catalysed by thermolysin. J Biotechnol 102 153-163 Tuchscherer G, Mutter M (1996) Template assisted protein de novo design. Pure Appl Chem 68(11) 2153-2162... 

The heats of ionisation and neutralisation of amino and hydroxylic bis and tris phosphonic acids have been investigated.253 Calorimetry in combination with u.v. and n.m.r. spectroscopy uas used to study the adducts of fluoroalkyl carboxylic acids with diethyl phosphonate.254 The heats of formation of the t-butoxytriphenylphosphoranyl radical uas consistent with the phosphonium structure (92).255 There has been a thermal analysis of the adducts of phosphonic and phosphoric acids with... 

P. Husek, P. Simek, P. Hartvich, H. Zahradnickova, Fluoroalkyl Chloroformates in Treating Amino Acids for Gas Chromatographic Analysis, Journal of Chromatography, A, 1186, 391 400 (2008). 

First, we consider the fluorinated analogues of natural amino acids, where at least one or several hydrogen atoms have been replaced by fluorine atoms. Then we consider amino acids substituted by a fluoroalkyl group, as the sole structural modification, with special focus on a-fluorinated amino acids. Lastly, we give an outline of polypeptides and proteins in which fluorinated amino acids have been incorporated. 

Amino acids with fluoroalkyl side chains have often been prepared for use in structural studies on the autoassembly of proteins. The presence of a highly hydrophobic substituent on the side chain, such as a fluoroalkyl group, of an amino acid of a polypeptide, may a priori deeply influence the interhelical interactions. 

Nonbranched amino acids substituted by a fluoroalkyl chain on a carbon distant at least one methylene from the amino acid function have been prepared as racemates by various methods." Under nonracemic form, co-perfluoroalkyl norvaline and norleucine (Rf = C2F5 or more) have been prepared by bromination of an anion of a fluorinated chiral oxazolidinone (derived from RfCH2CH2C02H). Substitution of the bromine atom by an azide and subsequent reduction yield the desired amino acids (Figure 5.10)." ... 

Free amino carboxylic acids65 and their ester derivatives66 can be added to fluoroalkylated alkynes to give amino acid derivatives. Fluoroalkynes and sodium azide afford, after thermal decomposition, the corresponding aziridines.67... 

The findings gained with the model system show that two contrary effects characterize the interactions of fluorinated amino acids within the hydrophobic core spatial demand and hydrophobicity on one side, and fluorine-induced polarity on the other. While the increase in hydrophobic surface area upon fluorination may be favorable for hydrophobic interactions, fluorine s inductive effect appears to interfere with the formation of an intact hydrophobic core. In addition, the investigations of fluoroalkyl side-chains in the charged domain as well as the analysis of fluorine s effect on replicase activity indicate that contacts between fluorinated residues may also have an impact on peptide and protein folding. 

Halogenoalkyl and Related Acids. - A wide range of a-fluoroalkyl-phosphonates have been prepared by a variety of methods (fluorinated amino acid analogues are discussed in 3.1.6). 

Bravo, P, Capelli, S., Meille, S.V., Seresini. P. Volonterio, A., and Zanda, M., Enantiomerically pure a-fluoroalkyl-a-amino acids. Synthesis of (R)-a-difluoromethyl-alanine and (S)-a-difluoromethyl-serine. Tetrahedron Asymmetry, 7, 2321. 1996. 

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